PROTAC Beyond Cancer- Exploring the New Therapeutic Potential of Proteolysis Targeting Chimeras

被引:4
作者
Bhole, Ritesh P. [1 ,2 ]
Patil, Sapana [1 ]
Kapare, Harshad S. [1 ]
Chikhale, Rupesh V. [3 ]
Gurav, Shailendra S. [4 ]
机构
[1] Dr DY Patil Inst Pharmaceut Sci & Res, Pune 411018, India
[2] Dr DY Patil Vidyappeth, DY Patil Dent Coll Hosp, Pune 411018, India
[3] UCL Sch Pharm, London, England
[4] Goa Coll Pharm, Dept Pharmacognosy, Panaji, Goa, India
关键词
PROTACs; High-throughput Imaging; CRBN engagement assays; Neurodegenerative disorders; Isothermal titration calorimetry assays; ATTENUATED INFLUENZA-VIRUS; PROTEIN-DEGRADATION; SMALL-MOLECULE; INSULIN-RESISTANCE; DESIGN; INHIBITION; DISCOVERY; UBIQUITINATION; PHOSPHORYLATION; IDENTIFICATION;
D O I
10.2174/0115680266309968240621072550
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
In the realm of oncology, the transformative impact of PROTAC (PROteolysis TAgeting Chimeras) technology has been particularly pronounced since its introduction in the 21st century. Initially conceived for cancer treatment, PROTACs have evolved beyond their primary scope, attracting increasing interest in addressing a diverse array of medical conditions. This expanded focus includes not only oncological disorders but also viral infections, bacterial ailments, immune dysregulation, neurodegenerative conditions, and metabolic disorders.This comprehensive review explores the broadening landscape of PROTAC application, highlighting ongoing developments and innovations aimed at deploying these molecules across a spectrum of diseases. Careful consideration of the design challenges associated with PROTACs reveals that, when appropriately addressed, these compounds present significant advantages over traditional therapeutic approaches, positioning them as promising alternatives.To evaluate the efficacy of PROTAC molecules, a diverse array of assays is employed, ranging from High-Throughput Imaging (HTI) assays to Cell Painting assays, CRBN engagement assays, Fluorescence Polarization assays, amplified luminescent proximity homogeneous assays, Time-resolved fluorescence energy transfer assays, and Isothermal Titration Calorimetry assays. These assessments collectively contribute to a nuanced understanding of PROTAC performance.Looking ahead, the trajectory of PROTAC technology suggests its potential recognition as a versatile therapeutic strategy for an expansive range of medical conditions. Ongoing progress in this field sets the stage for PROTACs to emerge as valuable tools in the multifaceted landscape of medical treatments.
引用
收藏
页码:2050 / 2073
页数:24
相关论文
共 140 条
[61]   Degradation versus Inhibition: Development of Proteolysis-Targeting Chimeras for Overcoming Statin-Induced Compensatory Upregulation of 3-Hydroxy-3-methylglutaryl Coenzyme A Reductase [J].
Li, Mei-Xin ;
Yang, Yiqing ;
Zhao, Qiuye ;
Wu, Yue ;
Song, Lei ;
Yang, Haiyan ;
He, Ming ;
Gao, Hongying ;
Song, Bao-Liang ;
Luo, Jie ;
Rao, Yu .
JOURNAL OF MEDICINAL CHEMISTRY, 2020, 63 (09) :4908-4928
[62]   Phthalimide conjugations for the degradation of oncogenic PI3K [J].
Li, Wenlu ;
Gao, Chunmei ;
Zhao, Lei ;
Yuan, Zigao ;
Chen, Yuzong ;
Jiang, Yuyang .
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 2018, 151 :237-247
[63]   PROTAC vaccine: A new way to live attenuated vaccines [J].
Li, Zhen ;
Bai, Haiqing ;
Xi, Xuetong ;
Tian, Wen-xia ;
Zhang, John Z. H. ;
Zhou, Demin ;
Si, Longlong .
CLINICAL AND TRANSLATIONAL MEDICINE, 2022, 12 (10)
[64]   Antiviral PROTACs: Opportunity borne with challenge [J].
Liang, Jinsen ;
Wu, Yihe ;
Lan, Ke ;
Dong, Chune ;
Wu, Shuwen ;
Li, Shu ;
Zhou, Hai-Bing .
CELL INSIGHT, 2023, 2 (03)
[65]   Assays and technologies for developing proteolysis targeting chimera degraders [J].
Liu, Xingui ;
Zhang, Xuan ;
Lv, Dongwen ;
Yuan, Yaxia ;
Zheng, Guangrong ;
Zhou, Daohong .
FUTURE MEDICINAL CHEMISTRY, 2020, 12 (12) :1155-1179
[66]   An overview of PROTACs: a promising drug discovery paradigm [J].
Liu, Zi ;
Hu, Mingxing ;
Yang, Yu ;
Du, Chenghao ;
Zhou, Haoxuan ;
Liu, Chengyali ;
Chen, Yuanwei ;
Fan, Lei ;
Ma, Hongqun ;
Gong, Youling ;
Xie, Yongmei .
MOLECULAR BIOMEDICINE, 2022, 3 (01)
[67]   Discovery of a Keap1-dependent peptide PROTAC to knockdown Tau by ubiquitination-proteasome degradation pathway [J].
Lu, Mengchen ;
Liu, Tian ;
Jiao, Qiong ;
Ji, Jianai ;
Tao, Mengmin ;
Liu, Yijun ;
You, Qidong ;
Jiang, Zhengyu .
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 2018, 146 :251-259
[68]   A cell-permeable peptide-based PROTAC against the oncoprotein CREPT proficiently inhibits pancreatic cancer [J].
Ma, Danhui ;
Zou, Yutian ;
Chu, Yunxiang ;
Liu, Zhengsheng ;
Liu, Gaochao ;
Chu, Jun ;
Li, Mengdi ;
Wang, Jiayu ;
Sun, Shi-yong ;
Chang, Zhijie .
THERANOSTICS, 2020, 10 (08) :3708-3721
[69]   Medicinal chemistry strategies for discovering antivirals effective against drug-resistant viruses [J].
Ma, Yue ;
Frutos-Beltran, Estrella ;
Kang, Dongwei ;
Pannecouque, Christophe ;
De Clercq, Erik ;
Menendez-Arias, Luis ;
Liu, Xinyong ;
Zhan, Peng .
CHEMICAL SOCIETY REVIEWS, 2021, 50 (07) :4514-4540
[70]   NanoBRET-A Novel BRET Platform for the Analysis of Protein-Protein Interactions [J].
Machleidt, Thomas ;
Woodroofe, Carolyn C. ;
Schwinn, Marie K. ;
Mendez, Jacqui ;
Robers, Matthew B. ;
Zirnmerman, Kris ;
Otto, Paul ;
Daniels, Danette L. ;
Kirkland, Thomas A. ;
Wood, Keith V. .
ACS CHEMICAL BIOLOGY, 2015, 10 (08) :1797-1804